Tight junctions (TJs) separate the internal space of multicellular organs and organisms from external compartments and form a paracellular diffusion barrier. TJs consist of a set of branched intramembranous strands of protein particles that bring the plasma membranes of opposing cells into molecular contact. Their main components are the different claudins, as well as occludin, marvelD3 and tricellulin; the latter three constitute the TJ-associated marvel protein (TAMP) family. However, not much is known with regard to the functions of the different TAMPs, or their interactions with claudins. In this study (p. 554), Ingolf Ernst Blasig and colleagues present a systematic analysis of the homophilic and heterophilic interactions formed by claudins and TAMPs using co-expression experiments in TJ-free HEK-293 cells. Fluorescence resonance energy transfer measurements show that all TAMPs can form homophilic cis-interactions at the plasma membrane, but these are weaker than the homophilic and heterophilic interactions of claudins. Furthermore, the authors find that heterophilic interactions occur between classic claudins and TAMPs that change TJ strand formation, as determined by freeze facture electron microscopy and mobility analysis. Taken together, these data suggest that claudins form the backbone of the TJ strands. The interactions of the claudins with TAMPs determine the behaviour of TAMPs, such as binding properties and localisation. By contrast, TAMPs improve the TJ strand network to obtain the typical physiological morphology of claudin TJ strands.